Publications by authors named "Julie van der Zee"

90 Publications

Family-based exome sequencing identifies RBM45 as a possible candidate gene for frontotemporal dementia and amyotrophic lateral sclerosis.

Neurobiol Dis 2021 Aug 9;156:105421. Epub 2021 Jun 9.

Neurodegenerative Brain Diseases, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium. Electronic address:

Neurodegenerative disorders like frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are pathologically characterized by toxic protein deposition in the cytoplasm or nucleus of affected neurons and glial cells. Many of these aggregated proteins belong to the class of RNA binding proteins (RBP), and, when mutated, account for a significant subset of familial ALS and FTD cases. Here, we present first genetic evidence for the RBP gene RBM45 in the FTD-ALS spectrum. RBM45 shows many parallels with other FTD-ALS associated genes and proteins. Multiple lines of evidence have demonstrated that RBM45 is an RBP that, upon mutation, redistributes to the cytoplasm where it co-aggregates with other RBPs into cytoplasmic stress granules (SG), evolving to persistent toxic TDP-43 immunoreactive inclusions. Exome sequencing in two affected first cousins of a heavily affected early-onset dementia family listed a number of candidate genes. The gene with the highest pathogenicity score was the RBP gene RBM45. In the family, the RBM45 Arg183* nonsense mutation co-segregated in both affected cousins. Validation in an unrelated patient (n = 548) / control (n = 734) cohort identified an additional RBM45 Arg183* carrier with bvFTD on a shared 4 Mb haplotype. Transcript and protein expression analysis demonstrated loss of nuclear RBM45, suggestive of a loss-of-function disease mechanism. Further, two more ultra-rare VUS, one in the nuclear localization signal (NLS, p.Lys456Arg) in an ALS patient and one in the intrinsically disordered homo-oligomer assembly (HOA) domain (p.Arg314Gln) in a patient with nfvPPA were detected. Our findings suggest that the pathomechanisms linking RBM45 with FTD and ALS may be related to its loss of nuclear function as a mediator of mRNA splicing, cytoplasmic retention or its inability to form homo-oligomers, leading to aggregate formation with trapping of other RBPs including TDP-43, which may accumulate into persisted TDP-43 inclusions.
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http://dx.doi.org/10.1016/j.nbd.2021.105421DOI Listing
August 2021

Investigation of the role of matrix metalloproteinases in the genetic etiology of Alzheimer's disease.

Neurobiol Aging 2021 Aug 28;104:105.e1-105.e6. Epub 2021 Mar 28.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium; Institute Born-Bunge, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium. Electronic address:

Matrix metalloproteinases (MMPs) are a multigene family of proteinases regulating the functions of a large number of signaling and scaffolding molecules that are involved in neuro-inflammation, synaptic dysfunction and neuronal death. MMPs have been associated with neurological conditions, such as Alzheimer's disease (AD), through a sudden and massive upregulation of particular members of the MMP family. Evidence for this hypothesis can be found in the clinical observation of increased MMP1 and MMP3 expression levels in plasma of AD patients compared to control individuals and in the pro-amyloidogenic effects that have been described for additional MMP family members like MMP13, MT1-MMP, and MT5-MMP. Consequently, we investigated the role of MMP1, 3, 13, MT1-MMP, and MT5-MMP in the genetic etiology of AD. We performed full exonic resequencing of these 5 MMPs in 1278 AD patients (mean age at onset [AAO]: 74.88 ± 9.10, range: 29-96) and 797 age-matched control individuals (mean age at inclusion [AAI]: 74.92 ± 6.48, range: 65-100) from Flanders-Belgium and identified MMP13 as most promising candidate gene. We identified 6 ultra-rare (≤0.01%) MMP13 missense mutations in 6 patients that were absent from the control cohort. We observed in one control individual a frameshift mutation (p.G269Qfs*2) leading to a premature termination codon. Based on previously described functional evidence, suggesting that MMP13 regulates BACE1 processing, and our genetic findings, we hypothesize a gain-of-function disease mechanism for the missense mutations found in patients. Functional experimental studies remain essential to assess the effect of these mutations on disease related processes and genetic replication studies are needed to corroborate our findings.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.03.011DOI Listing
August 2021

Emerging genetic complexity and rare genetic variants in neurodegenerative brain diseases.

Genome Med 2021 Apr 14;13(1):59. Epub 2021 Apr 14.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium.

Knowledge of the molecular etiology of neurodegenerative brain diseases (NBD) has substantially increased over the past three decades. Early genetic studies of NBD families identified rare and highly penetrant deleterious mutations in causal genes that segregate with disease. Large genome-wide association studies uncovered common genetic variants that influenced disease risk. Major developments in next-generation sequencing (NGS) technologies accelerated gene discoveries at an unprecedented rate and revealed novel pathways underlying NBD pathogenesis. NGS technology exposed large numbers of rare genetic variants of uncertain significance (VUS) in coding regions, highlighting the genetic complexity of NBD. Since experimental studies of these coding rare VUS are largely lacking, the potential contributions of VUS to NBD etiology remain unknown. In this review, we summarize novel findings in NBD genetic etiology driven by NGS and the impact of rare VUS on NBD etiology. We consider different mechanisms by which rare VUS can act and influence NBD pathophysiology and discuss why a better understanding of rare VUS is instrumental for deriving novel insights into the molecular complexity and heterogeneity of NBD. New knowledge might open avenues for effective personalized therapies.
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http://dx.doi.org/10.1186/s13073-021-00878-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048219PMC
April 2021

Sporadic Creutzfeldt-Jakob Disease and Other Proteinopathies in Comorbidity.

Front Neurol 2020 30;11:596108. Epub 2020 Nov 30.

Department of Pathology and Molecular Medicine, Third Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czechia.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common type of a group of transmissible spongiform encephalopathies (prion diseases). The etiology of the sporadic form of CJD is still unclear. sCJD can occur in combination with other neurodegenerative diseases, which further complicates the diagnosis. Alzheimer's disease (AD), e.g., is often seen in conjunction with sCJD. In this study, we performed a systematic analysis of 15 genes related to the most important neurodegenerative diseases - AD, frontotemporal dementia, amyotrophic lateral sclerosis, prion disease, and Parkinson's disease - in a cohort of sCJD and sCJD in comorbidity with AD and primary age-related proteinopathy (PART). A total of 30 neuropathologically verified cases of sCJD with and without additional proteinopathies were included in the study. In addition, we compared microtubule-associated protein tau haplotypes between sCJD patients and patients with sCJD and PART or sCJD and AD. Then we studied the interaction between the Apolipoprotein E gene ( and in sCJD patients. We did not find any causal mutations in the neurodegenerative disease genes. We did detect a p.E318G missense variant of uncertain significance (VUS) in in three patients. In , we also found a previously described non-pathogenic insertion (p.P84_Q91Q). Our pilot study failed to find any critical differences between pure sCJD and sCJD in conjunction with other comorbid neurodegenerative diseases. Further investigations are needed to better understand this phenomenon.
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http://dx.doi.org/10.3389/fneur.2020.596108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735378PMC
November 2020

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Neurobiol Aging 2021 03 2;99:99.e15-99.e22. Epub 2020 Sep 2.

Alzheimer's Disease and Other Cognitive Disorders Unit, Hospital Clínic, Fundació Clínic per a la Recerca Biomèdica, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.08.018DOI Listing
March 2021

, age at onset, and ancestry help discriminate behavioral from language variants in FTLD cohorts.

Neurology 2020 12 17;95(24):e3288-e3302. Epub 2020 Sep 17.

From the Institute of Neurology (B.C., D.A.K., J.H., P.A.L., R.F.), School of Pharmacy (C.M.), and UCL Movement Disorders Centre (J.H.), University College London; School of Pharmacy (C.M., P.A.L.), University of Reading, Whiteknights; Neurogenetics Laboratory (M.B.-Q., C.W., J.M.P.), National Hospital for Neurology and Neurosurgery, London, UK; Aptima Clinic (Miquel Aguilar), Terrassa; Memory Disorders Unit, Department of Neurology (I.A., M.D.-F., P.P.), University Hospital Mutua de Terrassa, Barcelona; Hospital Universitario Central de Asturias (V.A., M.M.-G.), Oviedo, Spain; NORMENT (O.A.), Institute of Clinical Medicine, University of Oslo, Norway; Regional Neurogenetic Centre (Maria Anfossi, Livia Bernardi, A.C.B., M.E.C., Chiara Cupidi, F.F., Maura Gallo, R.M., N.S.), ASPCZ, Lamezia Terme; Department of Neuroscience, Psychology, Drug Research and Child Health (S.B., B.N., I.P., S.S.), University of Florence; Molecular Markers Laboratory (Luisa Benussi, Giuliano Binetti, R.G.), IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy; Sheffield Institute for Translational Neuroscience (SITraN), Department of Neuroscience (D.B.), University of Sheffield, UK; Research Center and Memory Clinic (M.B., I.H., S.M.-G., Agustín Ruiz), Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya (UIC), Barcelona, Spain; Centre for Neurodegenerative Disorders (B.B., A.P.), Department of Clinical and Experimental Sciences, University of Brescia, Italy; Department of Clinical Neurosciences (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neurology (Geir Bråthen, S.B.S.), University Hospital of Trondheim, Norway; Dept NVS, Division of Neurogeriatrics (H.-H.C., C.G., B.K., L.Ö.), Karolinska Institutet, Bioclinicum Solna, Sweden; Department of Neurology (J.C., O.D.-I., I.I.-G., A.L.), IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Spain; Anne Rowling Regenerative Neurology Clinic (S.C., G.J.T.H., S.P.) and Centre for Clinical Brain Sciences (S.P.), University of Edinburgh, UK; NeuroGenomics and Informatics, Department of Psychiatry (Carlos Cruchaga), Washington University, St. Louis, MO; Cognitive Impairment Center (M.E.D.B., Maurizio Gallucci) and Immunohematology and Transfusional Medicine Service (E.D., A.V.), Local Health Authority n.2 Marca Trevigiana, Treviso, Italy; Department of Psychiatry and Psychotherapy (J.D.-S., C.R.), School of Medicine, Technical University of Munich, Germany; Department of Neurology (D.F., M.G.K.) and Clinical Institute of Medical Genetics (A.M., B.P.), University Medical Center Ljubljana, Slovenia; Dino Ferrari Center (D.G., Elio Scarpini, M.S.), University of Milan, Italy; Cognitive Neuroscience Lab, Think and Speak Lab (J.H.G.), Shirley Ryan Ability Lab, Chicago, IL; Department of Pathology and Laboratory Medicine (Murray Grossman, EunRan Suh, J.Q.T., V.M.V.D.), Center for Neurodegenerative Diseases, Perelman School of Medicine at the University of Pennsylvania, Philadelphia; UCL Dementia Research Institute (J.H.), London; Reta Lila Weston Institute (J.H.), UCL Queen Square Institute of Neurology, UK; Institute for Advanced Study (J.H.), The Hong Kong University of Science and Technology, China; Royal Edinburgh Hospital (G.J.T.H.), UK; Taub Institute for Research on Alzheimer's Disease and the Aging Brain (E.D.H.), Columbia University, New York, NY; Department of Neurology, Memory and Aging Center (A.K., B.M., J.Y.), University of California, San Francisco; UCL Genomics (M.K., G.K.M., Y.P.), UCL Great Ormond Street Institute of Child Health, London, UK; Geriatric Center Frullone ASL Napoli 1 Centro (G.M.), Napoli, Italy; Department of Neurology (M.O.M., J.v.R., J.C.V.S.), Erasmus Medical Center, Rotterdam, the Netherlands; Rona Holdings (P.M.), Silicon Valley, CA; Newcastle Brain Tissue Resource, Institute of Neuroscience (C.M.M.), Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne, UK; Department of Neurology (C.N.), Skåne University Hospital, Malmö, Sweden; Fondazione Policlinico Universitario A. Gemelli IRCCS (V.N.), Rome, Italy; Division of Neuroscience & Experimental Psychology (S.P.-B., A.M.T.R., S.R., J.C.T.), University of Manchester, UK; Amsterdam University Medical Center (Y.A.L.P.), VU University Medical Center, the Netherlands; Cardiovascular Research Unit (A.A.P.), IRCCS Multimedica, Milan; Neurology I, Department of Neuroscience (I.R., Elisa Rubino), University of Torino; NeurOMICS laboratory (G.M., Antonella Rendina, E.V.), Institute of Biochemistry and Cell Biology (IBBC), CNR Napoli, Italy; Manchester Centre for Clinical Neurosciences (A.M.T.R., J.S., J.C.T.), Salford Royal NHS Trust, Manchester, UK; Tanz Centre for Research in Neurodegenerative Diseases (Ekaterina Rogaeva), University of Toronto, Canada; Department of Biotechnology (B.R.), Jožef Stefan Institute, Ljubljana, Slovenia; Division of Neurology V and Neuropathology (G.R., F.T.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; Alzheimer's Disease and Other Cognitive Disorders Unit (R.S.-V.), Hospital Clínic of Barcelona, Spain; Clinical Memory Research Unit, Department of Clinical Sciences Malmö (C.N., A.F.S.), and Division of Clinical Sciences Helsingborg, Department of Clinical Sciences Lund (M.L.W.), Lund University, Sweden; Neurodegenerative Brain Diseases Group (J.V.d.Z., C.V.B.), Center for Molecular Neurology, VIB, Antwerp, Belgium; Medical Research Council Centre for Neuropsychiatric Genetics and Genomics (V.E.-P.), Division of Psychological Medicine and Clinical Neurosciences and Dementia Research Institute, Cardiff University, UK; Instituto de Investigación Sanitaria del Principado de Asturias (V.A.), Oviedo, Asturias; Fundació per la Recerca Biomèdica i Social Mútua Terrassa (I.A., M.D.-F., P.P.), Barcelona; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) (M.B., J.C., O.D.-I., I.H., I.I.-G., A.L., S.M.-G., Agustín Ruiz), Instituto de Salud Carlos III, Madrid, Spain; MRC Cognition and Brain Sciences Unit (Lucy Bowns, T.E.C., J.B.R.), Cambridge University, UK; Department of Neuromedicine and Movement Science (Geir Bråthen, S.B.S.), Norwegian University of Science and Technology, Trondheim, Norway; Unit for Hereditary Dementias (H.-H.C., C.G., B.K., L.Ö.), Theme Aging, Karolinska University Hospital, Solna, Sweden; Medical Faculty (D.F., M.G.K.), University of Ljubljana, Slovenia; Fondazione IRCCS Ca'Granda (D.G., Elio Scarpini, M.S.), Ospedale Policlinico, Milan, Italy; Penn Center for Frontotemporal Degeneration (Murray Grossman), Philadelphia, PA; Universidad de Oviedo (M.M.-G.), Asturias, Spain; IRCCS Fondazione Don Carlo Gnocchi (B.N., S.S.), Florence; Istituto di Medicina Genomica (V.N.), Università Cattolica del sacro Cuore, Rome, Italy; Amsterdam Neuroscience (Y.A.L.P.), the Netherlands; Department of Medicine and Surgery (A.A.P.), University of Salerno, Baronissi (SA), Italy; Faculty of Chemistry and Chemical Technology (B.R.), University of Ljubljana, Slovenia; Institud d'Investigacions Biomèdiques August Pi i Sunyer (R.S.-V.), Barcelona, Spain; Department of Biomedical Sciences (J.V.d.Z., C.V.B.), University of Antwerp, Belgium; and Department of Comparative Biomedical Sciences (P.A.L.), The Royal Veterinary College, London, UK.

Objective: We sought to characterize expansions in relation to genetic ancestry and age at onset (AAO) and to use these measures to discriminate the behavioral from the language variant syndrome in a large pan-European cohort of frontotemporal lobar degeneration (FTLD) cases.

Methods: We evaluated expansions frequency in the entire cohort (n = 1,396; behavioral variant frontotemporal dementia [bvFTD] [n = 800], primary progressive aphasia [PPA] [n = 495], and FTLD-motor neuron disease [MND] [n = 101]). We then focused on the bvFTD and PPA cases and tested for association between expansion status, syndromes, genetic ancestry, and AAO applying statistical tests comprising Fisher exact tests, analysis of variance with Tukey post hoc tests, and logistic and nonlinear mixed-effects model regressions.

Results: We found pathogenic expansions in 4% of all cases (56/1,396). Expansion carriers differently distributed across syndromes: 12/101 FTLD-MND (11.9%), 40/800 bvFTD (5%), and 4/495 PPA (0.8%). While addressing population substructure through principal components analysis (PCA), we defined 2 patients groups with Central/Northern (n = 873) and Southern European (n = 523) ancestry. The proportion of expansion carriers was significantly higher in bvFTD compared to PPA (5% vs 0.8% [ = 2.17 × 10; odds ratio (OR) 6.4; confidence interval (CI) 2.31-24.99]), as well as in individuals with Central/Northern European compared to Southern European ancestry (4.4% vs 1.8% [ = 1.1 × 10; OR 2.5; CI 1.17-5.99]). Pathogenic expansions and Central/Northern European ancestry independently and inversely correlated with AAO. Our prediction model (based on expansions status, genetic ancestry, and AAO) predicted a diagnosis of bvFTD with 64% accuracy.

Conclusions: Our results indicate correlation between pathogenic expansions, AAO, PCA-based Central/Northern European ancestry, and a diagnosis of bvFTD, implying complex genetic risk architectures differently underpinning the behavioral and language variant syndromes.
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http://dx.doi.org/10.1212/WNL.0000000000010914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836664PMC
December 2020

No association of CpG SNP rs9357140 with onset age in Belgian C9orf72 repeat expansion carriers.

Neurobiol Aging 2021 01 15;97:145.e1-145.e4. Epub 2020 Aug 15.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

We investigated the impact of the recently described chromosome 6 open reading frame 10 (C6orf10)/LOC101929163 locus as age-at-onset modifier in an extended cohort of Belgian chromosome 9 open reading frame 72 (C9orf72) GC repeat expansion carriers. We genotyped the tagging CpG single-nucleotide polymorphism rs9357140 in 224 confirmed C9orf72 repeat expansion carriers, 102 index cases and 122 relatives, and tested association with onset age. The C9orf72 repeat expansion cohort consisted of 131 symptomatic carriers, that is, 78 with dementia only, 13 with frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS), and 40 ALS only, and 93 presymptomatic carriers. Cox proportional hazard regression analysis failed to identify significant association (adjusted hazard ratio = 1.15, p = 0.3). We further extended our analysis to a Belgian cohort of unrelated, mutation-negative FTD index patients (n = 230), but also found no association (adjusted hazard ratio = 0.96, p = 0.3). Overall, our findings suggest that in the Belgian cohort, the C6orf10/LOC101929163 locus cannot explain the marked variability in age at onset, and other genetic or environmental modifiers must drive the clinical heterogeneity observed among C9orf72 repeat expansion carriers.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.07.021DOI Listing
January 2021

Amyloid-β cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations.

Alzheimers Res Ther 2020 09 11;12(1):108. Epub 2020 Sep 11.

Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, Antwerp, Belgium.

Background: Alzheimer's disease (AD) mutations in amyloid precursor protein (APP) and presenilins (PSENs) could potentially lead to the production of longer amyloidogenic Aβ peptides. Amongst these, Aβ is more prone to aggregation and has higher toxic properties than the long-known Aβ. However, a direct effect on Aβ in biomaterials of individuals carrying genetic mutations in the known AD genes is yet to be determined.

Methods: N = 1431 AD patients (n = 280 early-onset (EO) and n = 1151 late-onset (LO) AD) and 809 control individuals were genetically screened for APP and PSENs. For the first time, Aβ levels were analysed in cerebrospinal fluid (CSF) of 38 individuals carrying pathogenic or unclear rare mutations or the common PSEN1 p.E318G variant and compared with Aβ and Aβ CSF levels. The soluble sAPPα and sAPPβ species were also measured for the first time in mutation carriers.

Results: A known pathogenic mutation was identified in 5.7% of EOAD patients (4.6% PSEN1, 1.07% APP) and in 0.3% of LOAD patients. Furthermore, 12 known variants with unclear pathogenicity and 11 novel were identified. Pathogenic and unclear mutation carriers showed a significant reduction in CSF Aβ levels compared to controls (p = 0.037; < 0.001). CSF Aβ levels positively correlated with CSF Aβ in both pathogenic and unclear carriers and controls (all p < 0.001). The p.E318G carriers showed reduced Aβ levels (p < 0.001), though genetic association with AD was not detected. sAPPα and sAPPβ CSF levels were significantly reduced in the group of unclear (p = 0.006; 0.005) and p.E318G carriers (p = 0.004; 0.039), suggesting their possible involvement in AD. Finally, using Aβ and Aβ levels, we could re-classify as "likely pathogenic" 3 of the unclear mutations.

Conclusion: This is the first time that Aβ levels were analysed in CSF of AD patients with genetic mutations in the AD causal genes. The observed reduction of Aβ in APP and PSENs carriers highlights the pathogenic role of longer Aβ peptides in AD pathogenesis. Alterations in Aβ could prove useful in understanding the pathogenicity of unclear APP and PSENs variants, a critical step towards a more efficient genetic counselling.
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http://dx.doi.org/10.1186/s13195-020-00676-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488767PMC
September 2020

Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease.

Neurobiol Aging 2020 03 1;87:139.e1-139.e7. Epub 2019 Nov 1.

Movement Disorders Unit, Neurology Department, Hospital General Universitario Gregorio Maranon, Madrid, Spain.

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.10.017DOI Listing
March 2020

Stress granule mediated protein aggregation and underlying gene defects in the FTD-ALS spectrum.

Neurobiol Dis 2020 02 15;134:104639. Epub 2019 Oct 15.

Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

Stress granules (SGs) are dynamic membraneless compartments composed out of RNA-binding proteins (RBPs) and RNA molecules that assemble temporarily to allow the cell to cope with cellular stress by stalling mRNA translation and moving synthesis towards cytoprotective proteins. Aberrant SGs have become prime suspects in the nucleation of toxic protein aggregation in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Perturbed SG dynamics appears to be mediated by alterations in RNA binding proteins (RBP). Indeed, a growing number of FTD and/or ALS related RBPs coding genes (TDP43, FUS, EWSR1, TAF15, hnRNPA1, hnRNPA2B1, ATXN2, TIA1) have been identified to interfere with SG formation through mutation of their low-complexity domain (LCD), and thereby cause or influence disease. Interestingly, disease pathways associated to the C9orf72 repeat expansion, the leading genetic cause of the FTD-ALS spectrum, intersect with SG-mediated protein aggregate formation. In this review, we provide a comprehensive overview of known SG proteins and their genetic contribution to the FTD-ALS spectrum. Importantly, multiple LCD-baring RBPs have already been identified in FTD-ALS that have not yet been genetically linked to disease. These should be considered candidate genes and offer opportunities for gene prioritization when mining sequencing data of unresolved FTD and ALS. Further, we zoom into the current understanding of the molecular processes of perturbed RBP function leading to disturbed SG dynamics, RNA metabolism, and pathological inclusions. Finally, we indicate how these gained insights open new avenues for therapeutic strategies targeting phase separation and SG dynamics to reverse pathological protein aggregation and protect against toxicity.
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http://dx.doi.org/10.1016/j.nbd.2019.104639DOI Listing
February 2020

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability.

Acta Neuropathol 2019 06 14;137(6):901-918. Epub 2019 Mar 14.

Center for Molecular Neurology, VIB, Antwerp, Belgium.

Emerging evidence suggested a converging mechanism in neurodegenerative brain diseases (NBD) involving early neuronal network dysfunctions and alterations in the homeostasis of neuronal firing as culprits of neurodegeneration. In this study, we used paired-end short-read and direct long-read whole genome sequencing to investigate an unresolved autosomal dominant dementia family significantly linked to 7q36. We identified and validated a chromosomal inversion of ca. 4 Mb, segregating on the disease haplotype and disrupting the coding sequence of dipeptidyl-peptidase 6 gene (DPP6). DPP6 resequencing identified significantly more rare variants-nonsense, frameshift, and missense-in early-onset Alzheimer's disease (EOAD, p value = 0.03, OR = 2.21 95% CI 1.05-4.82) and frontotemporal dementia (FTD, p = 0.006, OR = 2.59, 95% CI 1.28-5.49) patient cohorts. DPP6 is a type II transmembrane protein with a highly structured extracellular domain and is mainly expressed in brain, where it binds to the potassium channel K4.2 enhancing its expression, regulating its gating properties and controlling the dendritic excitability of hippocampal neurons. Using in vitro modeling, we showed that the missense variants found in patients destabilize DPP6 and reduce its membrane expression (p < 0.001 and p < 0.0001) leading to a loss of protein. Reduced DPP6 and/or K4.2 expression was also detected in brain tissue of missense variant carriers. Loss of DPP6 is known to cause neuronal hyperexcitability and behavioral alterations in Dpp6-KO mice. Taken together, the results of our genomic, genetic, expression and modeling analyses, provided direct evidence supporting the involvement of DPP6 loss in dementia. We propose that loss of function variants have a higher penetrance and disease impact, whereas the missense variants have a variable risk contribution to disease that can vary from high to low penetrance. Our findings of DPP6, as novel gene in dementia, strengthen the involvement of neuronal hyperexcitability and alteration in the homeostasis of neuronal firing as a disease mechanism to further investigate.
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http://dx.doi.org/10.1007/s00401-019-01976-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531610PMC
June 2019

Presence of tau astrogliopathy in frontotemporal dementia caused by a novel Grn nonsense (Trp2*) mutation.

Neurobiol Aging 2019 04 20;76:214.e11-214.e15. Epub 2018 Nov 20.

Brain Tissue Bank, Fundación CIEN, Instituto de Salud Carlos III, Madrid, Spain.

Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions. Some neurofibrillary tangles and pretangles, both 3R and 4R(+), were present in the medial temporal lobe but did not exhibit the characteristic distribution of Alzheimer's type pathology. This 4R-tau aging-related tau astrogliopathy is likely a co-occurring pathology, although an interaction between progranulin and tau proteins within the neurodegenerative process should not be ruled out.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.11.010DOI Listing
April 2019

A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.

Brain 2018 10;141(10):2895-2907

Neurodegenerative Brain Diseases, Center of Molecular Neurology, VIB, Antwerp, Belgium.

The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
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http://dx.doi.org/10.1093/brain/awy238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158742PMC
October 2018

Systematic Screening of Ubiquitin/p62 Aggregates in Cerebellar Cortex Expands the Neuropathological Phenotype of the C9orf72 Expansion Mutation.

J Neuropathol Exp Neurol 2018 08;77(8):703-709

Neurological Tissue Bank of the Biobanc-Hospital Clinic-IDIBAPS, Barcelona, Spain.

The neuropathological hallmark of the C9orf72 intronic hexanucleotide expansion in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) is the presence of small ubiquitin/p62-positive and transactive response DNA binding protein 43 kDa (TDP-43)-negative cytoplasmic inclusions in several brain areas. The identification of this histopathological signature is highly predictive of an underlying mutation. In this study, we screened 1800 cases of the Barcelona IDIBAPS Brain Bank, independently of the clinical and final neuropathological diagnosis of the brain donor, for the presence of ubiquitin/p62-positive inclusions in the cerebellum (UPPI). Positive cases were also stained for dipeptide repeats. We identified a total of 21 donors with UPPI and in all of them the C9orf72 hexanucleotide expansion was genetically confirmed. Most donors had an FTLD or to a lesser extent ALS clinico-pathological phenotype. However, 3 cases had been previously classified as having clinically and neuropathologically Lewy body disease. Other co-existing pathologies, especially of the PART-type, were also frequently encountered. This study highlights the importance of the evaluation of ubiquitin/p62-positive cytoplasmic inclusions in all neurodegenerative diseases as a good screening method for the detection of C9orf72 expansion mutation, since this mutation is not rare and can overlap with other neurodegenerative entities.
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http://dx.doi.org/10.1093/jnen/nly047DOI Listing
August 2018

No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients.

Neurobiol Aging 2018 09 23;69:293.e9-293.e11. Epub 2018 May 23.

Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.05.005DOI Listing
September 2018

Genetic screening in early-onset dementia patients with unclear phenotype: relevance for clinical diagnosis.

Neurobiol Aging 2018 09 9;69:292.e7-292.e14. Epub 2018 May 9.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

In a prospective study of dementia in Flanders (Belgium), we observed a substantial fraction of early-onset dementia patients who did not fulfill the criteria for a specific dementia subtype, leaving the patients without a precise clinical diagnosis. We selected 211 of these patients for genetic testing of causal genes linked to neurodegenerative brain diseases. In this group, the onset or inclusion age was 59.9 ± 8.2 years and 27.4% had a positive family history. We used a panel of 16 major genes linked to Alzheimer's disease, frontotemporal dementia, amyotrophic lateral sclerosis, Parkinson's disease, and prion diseases. In addition, we tested for the presence of a pathogenic C9orf72 repeat expansion. We identified 13 rare variants in 15 patients, including a carrier of variants in 2 different genes. Six patients (2.84%), carried a mutation in a Mendelian causal gene, that is, APP, MAPT, SOD1, TBK1, and C9orf72. In the other 7 patients, 7 variants were of uncertain significance, including a frameshift mutation in PSEN2, p.G359Lfs*74, in 2 patients sharing a common haplotype, and in LRRK2, p.L2063fs*. Expression studies showed reduced PSEN2 and a near complete loss of LRRK2, in lymphoblast cells or brain material of these patients. Overall, our study underscores the relevance of genetic testing of known causal genes in early-onset patients with symptomatology of neurodegenerative dementia but an unclear clinical diagnosis. A positive genetic result can help to obtain a precise diagnosis as well as a better understanding of the presence of multiple affected relatives in the family.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.04.015DOI Listing
September 2018

A novel CHCHD10 mutation implicates a Mia40-dependent mitochondrial import deficit in ALS.

EMBO Mol Med 2018 06;10(6)

German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany

mutations are linked to amyotrophic lateral sclerosis, but their mode of action is unclear. In a 29-year-old patient with rapid disease progression, we discovered a novel mutation (Q108P) in a conserved residue within the coiled-coil-helix-coiled-coil-helix (CHCH) domain. The aggressive clinical phenotype prompted us to probe its pathogenicity. Unlike the wild-type protein, mitochondrial import of CHCHD10 Q108P was blocked nearly completely resulting in diffuse cytoplasmic localization and reduced stability. Other CHCHD10 variants reported in patients showed impaired mitochondrial import (C122R) or clustering within mitochondria (especially G66V and E127K) often associated with reduced expression. Truncation experiments suggest mitochondrial import of CHCHD10 is mediated by the CHCH domain rather than the proposed N-terminal mitochondrial targeting signal. Knockdown of Mia40, which introduces disulfide bonds into CHCH domain proteins, blocked mitochondrial import of CHCHD10. Overexpression of Mia40 rescued mitochondrial import of CHCHD10 Q108P by enhancing disulfide-bond formation. Since reduction in CHCHD10 inhibits respiration, mutations in its CHCH domain may cause aggressive disease by impairing mitochondrial import. Our data suggest Mia40 upregulation as a potential therapeutic salvage pathway.
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http://dx.doi.org/10.15252/emmm.201708558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991575PMC
June 2018

Genotype-phenotype links in frontotemporal lobar degeneration.

Nat Rev Neurol 2018 06;14(6):363-378

Neurodegenerative Brain Diseases Group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium.

Frontotemporal lobar degeneration (FTLD) represents a group of neurodegenerative brain diseases with highly heterogeneous clinical, neuropathological and genetic characteristics. This high degree of heterogeneity results from the presence of several different underlying molecular disease processes; consequently, it is unlikely that all patients with FTLD will benefit from a single therapy. Therapeutic strategies for FTLD are currently being explored, and tools are urgently needed that enable the selection of patients who are the most likely to benefit from a particular therapy. Definition of the phenotypic characteristics in patients with different FTLD subtypes that share the same underlying disease processes would assist in the stratification of patients into homogeneous groups. The most common subtype of FTLD is characterized by TAR DNA-binding protein 43 (TDP43) pathology (FTLD-TDP). In this group, pathogenic mutations have been identified in four genes: C9orf72, GRN, TBK1 and VCP. Here, we provide a comprehensive overview of the phenotypic characteristics of patients with FTLD-TDP, highlighting shared features and differences among groups of patients who have a pathogenic mutation in one of these four genes.
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http://dx.doi.org/10.1038/s41582-018-0009-8DOI Listing
June 2018

Clinical variability and onset age modifiers in an extended Belgian GRN founder family.

Neurobiol Aging 2018 07 10;67:84-94. Epub 2018 Mar 10.

Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge and University of Antwerp, Antwerp, Belgium. Electronic address:

We previously reported a granulin (GRN) null mutation, originating from a common founder, in multiple Belgian families with frontotemporal dementia. Here, we used data of a 10-year follow-up study to describe in detail the clinical heterogeneity observed in this extended founder pedigree. We identified 85 patients and 40 unaffected mutation carriers, belonging to 29 branches of the founder pedigree. Most patients (74.4%) were diagnosed with frontotemporal dementia, while others had a clinical diagnosis of unspecified dementia, Alzheimer's dementia or Parkinson's disease. The observed clinical heterogeneity can guide clinical diagnosis, genetic testing, and counseling of mutation carriers. Onset of initial symptomatology is highly variable, ranging from age 45 to 80 years. Analysis of known modifiers, suggested effects of GRN rs5848, microtubule-associated protein tau H1/H2, and chromosome 9 open reading frame 72 GC repeat length on onset age but explained only a minor fraction of the variability. Contrary, the extended GRN founder family is a valuable source for identifying other onset age modifiers based on exome or genome sequences. These modifiers might be interesting targets for developing disease-modifying therapies.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.03.007DOI Listing
July 2018

ALS Genes in the Genomic Era and their Implications for FTD.

Trends Genet 2018 06 28;34(6):404-423. Epub 2018 Mar 28.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy.
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http://dx.doi.org/10.1016/j.tig.2018.03.001DOI Listing
June 2018

Diagnostic value of cerebrospinal fluid tau, neurofilament, and progranulin in definite frontotemporal lobar degeneration.

Alzheimers Res Ther 2018 03 20;10(1):31. Epub 2018 Mar 20.

Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Background: We explored the diagnostic performance of cerebrospinal fluid (CSF) biomarkers in allowing differentiation between frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD), as well as between FTLD pathological subtypes.

Methods: CSF levels of routine AD biomarkers (phosphorylated tau (p-tau), total tau (t-tau), and amyloid-beta (Aβ)) and neurofilament proteins, as well as progranulin levels in both CSF and serum were quantified in definite FTLD (n = 46), clinical AD (n = 45), and cognitively healthy controls (n = 20). FTLD subgroups were defined by genetic carrier status and/or postmortem neuropathological confirmation (FTLD-TDP: n = 34, including FTLD-C9orf72: n = 19 and FTLD-GRN: n = 9; FTLD-tau: n = 10).

Results: GRN mutation carriers had significantly lower progranulin levels compared to other FTLD patients, AD, and controls. Both t-tau and p-tau were normal in FTLD patients, even in FTLD-tau. Aβ levels were very variable in FTLD. Neurofilament light chain (Nf-L) was significantly higher in FTLD compared with AD and controls. The reference logistic regression model based on the established AD biomarkers could be improved by the inclusion of CSF Nf-L, which was also important for the differentiation between FTLD and controls. Within the FTLD cohort, no significant differences were found between FTLD-TDP and FTLD-tau, but GRN mutation carriers had higher t-tau and Nf-L levels than C9orf72 mutation carriers and FTLD-tau patients.

Conclusions: There is an added value for Nf-L in the differential diagnosis of FTLD. Progranulin levels in CSF depend on mutation status, and GRN mutation carriers seem to be affected by more severe neurodegeneration.
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http://dx.doi.org/10.1186/s13195-018-0364-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859717PMC
March 2018

Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia.

Neurobiol Aging 2018 06 17;66:181.e3-181.e10. Epub 2018 Feb 17.

Hôpitaux Universitaires de Genève et Université de Genève, Geneva, Switzerland; IRCCS Fatebenefratelli, Brescia, Italy.

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.02.011DOI Listing
June 2018

Extended FTLD pedigree segregating a Belgian GRN-null mutation: neuropathological heterogeneity in one family.

Alzheimers Res Ther 2018 01 22;10(1). Epub 2018 Jan 22.

Institute Born-Bunge, Neuropathology and Laboratory of Neurochemistry and Behavior, University of Antwerp, Universiteitsplein 1, B-2160, Antwerp, Belgium.

Background: In this paper, we describe the clinical and neuropathological findings of nine members of the Belgian progranulin gene (GRN) founder family. In this family, the loss-of-function mutation IVS1 + 5G > C was identified in 2006. In 2007, a clinical description of the mutation carriers was published that revealed the clinical heterogeneity among IVS1 + 5G > C carriers. We report our comparison of our data with the published clinical and neuropathological characteristics of other GRN mutations as well as other frontotemporal lobar degeneration (FTLD) syndromes, and we present a review of the literature.

Methods: For each case, standardized sampling and staining were performed to identify proteinopathies, cerebrovascular disease, and hippocampal sclerosis.

Results: The neuropathological substrate in the studied family was compatible in all cases with transactive response DNA-binding protein (TDP) proteinopathy type A, as expected. Additionally, most of the cases presented also with primary age-related tauopathy (PART) or mild Alzheimer's disease (AD) neuropathological changes, and one case had extensive Lewy body pathology. An additional finding was the presence of cerebral small vessel changes in every patient in this family.

Conclusions: Our data show not only that the IVS1 + 5G > C mutation has an exclusive association with FTLD-TDP type A proteinopathy but also that other proteinopathies can occur and should be looked for. Because the penetrance rate of the clinical phenotype of carriers of GRN mutations is age-dependent, further research is required to investigate the role of co-occurring age-related pathologies such as AD, PART, and cerebral small vessel disease.
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http://dx.doi.org/10.1186/s13195-017-0334-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6389176PMC
January 2018

Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort.

Neurobiol Aging 2018 02 25;62:245.e1-245.e7. Epub 2017 Oct 25.

Neurodegenerative Brain Diseases group, VIB Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium; Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.10.012DOI Listing
February 2018

NEK1 genetic variability in a Belgian cohort of ALS and ALS-FTD patients.

Neurobiol Aging 2018 01 31;61:255.e1-255.e7. Epub 2017 Aug 31.

Neurodegenerative Brain Diseases Group, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

We evaluated the genetic impact of the amyotrophic lateral sclerosis (ALS) risk gene never in mitosis gene a-related kinase 1 (NEK1) in a Belgian cohort of 278 patients with ALS (n = 245) or ALS with frontotemporal dementia (ALS-FTD, n = 33) and 609 control individuals. We identified 2 ALS patients carrying a loss-of-function (LOF) mutation, p.Leu854Tyrfs*2 and p.Tyr871Valfs*17, that was absent in the control group. A third LOF variant p.Ser1036* was present in 2 sibs with familial ALS but also in an unrelated control person. Missense variants were common in both patients (3.6%) and controls (3.0%). The missense variant, p.Arg261His, which was previously associated with ALS risk, was detected with a minor allele frequency of 0.90% in patients compared to 0.33% in controls. Taken together, NEK1 LOF variants accounted for 1.1% of patients, although interpretation of pathogenicity and penetrance is complicated by the observation of occasional LOF variants in unaffected individuals (0.16%). Furthermore, enrichment of additional ALS gene mutations was observed in NEK1 carriers, suggestive of a "second hit" model were NEK1 variants may modify disease presentation of driving mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.08.021DOI Listing
January 2018

Modifiers of GRN-Associated Frontotemporal Lobar Degeneration.

Trends Mol Med 2017 10 7;23(10):962-979. Epub 2017 Sep 7.

Neurodegenerative Brain Diseases, Center for Molecular Neurology, VIB, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address:

Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.
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http://dx.doi.org/10.1016/j.molmed.2017.08.004DOI Listing
October 2017

No added diagnostic value of non-phosphorylated tau fraction (p-tau) in CSF as a biomarker for differential dementia diagnosis.

Alzheimers Res Ther 2017 Jul 14;9(1):49. Epub 2017 Jul 14.

Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk, Belgium.

Background: The Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ, t-tau, and p-tau overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-tau), may improve differential dementia diagnosis. The goal of this study is to investigate if p-tau can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis.

Methods: The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ, t-tau, p-tau, and p-tau were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests.

Results: The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-tau to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-tau increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-tau when differentiating between AD or non-AD dementias and controls.

Conclusions: The addition of p-tau to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias.
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http://dx.doi.org/10.1186/s13195-017-0275-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513364PMC
July 2017

Deleterious ABCA7 mutations and transcript rescue mechanisms in early onset Alzheimer's disease.

Acta Neuropathol 2017 Sep 27;134(3):475-487. Epub 2017 Apr 27.

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.
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http://dx.doi.org/10.1007/s00401-017-1714-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5563332PMC
September 2017
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